There is a continuing need to identify chemopreventive drugs for cancer, as most identified so far have shown effects on only one type of cancer and/or have been associated with some adverse effects. Glucosamine and chondroitin (G & C), often taken together in a single pill, are the most commonly used specialty (non-vitamin, non-mineral) supplement in the US. Randomized trials support their efficacy for arthritis. Laboratory studies show that G & C both inhibit the transcription factor NF-kappa B, which leads to decreased inflammatory response to stimuli and inhibition of cell proliferation, effects associated with lower cancer risk. Other anti-inflammatory drugs (e.g., aspirin) have been shown in some studies to reduce the risk of colorectal, breast, prostate, lung, and total cancer, but may have adverse effects. However, there are no human studies of G & C in relation to cancer risk. Furthermore, while these supplements are considered to be safe, the small sample sizes (20-952 users of G &/or C) and short durations (<=24 months) of G & C use in prior studies suggests that adverse effects have not been fully assessed. The VITamins And Lifestyle (VITAL) study is a prospective study which targeted supplement users in recruitment. From 2000-2002, 77,738 men and women in western Washington State, age 50-76, entered the cohort, by completing a detailed questionnaire on use of 38 supplements over the past 10 years, diet, and lifestyle factors. Over 15,600 participants used glucosamine, and over 10,400 used chondroitin. Participants are followed for outcomes using cost-effective linkages to databases. In exploratory studies of multiple supplements in relation to three outcomes, G & C were each associated with a 20-35% statistically significant reduced risk of lung cancer, colorectal cancer and total mortality. These are the strongest and most consistent findings across endpoints of a benefit of any supplement examined thus far in this cohort. The aims of this proposed project are to investigate the associations of intake of G & C with risk of breast cancer, prostate cancer, total cancer, and with lung and colorectal cancer in more detail, including examination of frequency/duration of G & C use, effect modification by factors associated with inflammation, and differential effects by cancer characteristics (Aim 1). Additional aims are to investigate the associations of G & C with cancer mortality (Aim 2) and with other cause-specific mortality to identity other major adverse or beneficial effects (Aim 3), and to test in a pilot study biomarkers of the mechanisms by which G & C may reduce risk of disease, including serum IL-1beta, IL-6, IL-10, TNFalpha, sTNF-RI, sTNF-RII, CRP, and SAA (Aim 4). Aims 1-3 will be accomplished by continued follow-up of the VITAL cohort for three additional years to increase study power, and by more detailed and focused data analyses of the outcomes in relation to G & C use. We expect a total of 10,200 cancers and 5700 deaths. 220 men and women who participated in a prior home interview, supplement inventory and blood draw will provide the materials for Aim 4. PUBLIC HEALTH RELEVANCE: This study would provide information to help guide the American public about the benefits and risks of taking glucosamine and chondroitin supplements. In addition, if there are observed protective associations of glucosamine and/or chondroitin with cancer risk and no major adverse effects, then these supplements would deserve further investigation as cancer preventive drugs.